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Abstract The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19. In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and their human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed the impact of missense variants occurring in the protein–protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities for the human viral protein complexes. We predicted a total of 26 affinity-enhancing variants from 13 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed. Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.

Abstract Perineural invasion (PNI) is frequently associated with aggressive clinical behaviour in head and neck cutaneous squamous cell carcinoma (HNcSCC) leading to local recurrence and treatment failure. This study evaluates the gene expression profiles of HNcSCC with PNI using a differential expression analysis approach and constructs a tailored gene panel for sensitivity and specificity analysis. 45 cases of HNcSCC were stratified into three groups (Extensive, Focal and Non PNI) based on predefined clinicopathological criteria. Here we show HNcSCC with extensive PNI demonstrates significant up- and down-regulation of 144 genes associated with extracellular matrix interactions, epithelial to mesenchymal transition, cell adhesion, cellular motility, angiogenesis, and cellular differentiation. Gene expression of focal and non PNI cohorts were indistinguishable and were combined for further analyses. There is clinicopathological correlation between gene expression analysis findings and disease behaviour and a tailored panel of 10 genes was able to identify extensive PNI with 96% sensitivity and 95% specificity.

Abstract Incidence of hip fractures has remained unchanged during the pandemic with overlapping vulnerabilities observed in patients with hip fractures and those infected with COVID-19. We aimed to investigate the independent impact of COVID-19 infection on the mortality of these patients. Healthcare databases were systematically searched over 2-weeks from 1st–14th November 2020 to identify eligible studies assessing the impact of COVID-19 on hip fracture patients. Meta-analysis of proportion was performed to obtain pooled values of prevalence, incidence and case fatality rate of hip fracture patients with COVID-19 infection. 30-day mortality, excess mortality and all-cause mortality were analysed using a mixed-effects model. 22 studies reporting 4015 patients were identified out of which 2651 (66%) were assessed during the pandemic. An excess mortality of 10% was seen for hip fractures treated during the pandemic (OR 2.00, p = 0.007), in comparison to the pre-pandemic controls (5%). Estimated mortality of COVID-19 positive hip fracture patients was four-fold (RR 4.59, p

Abstract Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.